Mechanism for the Transit-Induced Increase in Colonic Deoxycholic Acid Formation in Cholesterol Cholelithiasis

Gastroenterology. 2000 Sep;119(3):806-15. doi: 10.1053/gast.2000.16495.

Abstract

Background & aims: Many patients with cholesterol gallbladder stones (GBS) have a high percentage of deoxycholic acid (DCA) in gallbladder bile (all of which are in the conjugated form), probably as a result of prolonged large bowel transit times (LBTT). However, whether the prolonged LBTT increases DCA formation, solubilization, or absorption (or all 3) is not known.

Methods: In 40 subjects (20 with GBS; age range, 24-74 years), we measured LBTT using radiopaque markers, and intestinal luminal pH by radiotelemetry. We also measured quantitative anaerobic bacteriology and the activities of 2 bile acid-metabolizing enzymes in fresh cecal aspirates obtained during clinically indicated unprepared colonoscopy, and related these results to the percentage of DCA in fasting serum measured by gas chromatography-mass spectrometry.

Results: Compared with controls, GBS patients had longer LBTT (mean 23.1 +/- SEM 2.8 h vs. 36.5 +/- 3.3 h; P < 0.01); more total (2.7 +/- 0.6 x 10(9) vs. 5.9 +/- 1.5 x 10(9) cfu/mL) and Gram-positive (9.5 +/- 3.1 x 10(8) vs. 18.0 +/- 4.1 x 10(8) cfu/mL; P < 0.05) anaerobes; and greater 7alpha-dehydroxylating (7alpha-DH) activity (3.39 +/- 0.59 vs. 10.37 +/- 1.15 x 10(-4) U/mg protein) in the cecal aspirates. They also had higher intracolonic pH values (P < 0.02) and increased percentages of DCA in fasting serum (13.4% +/- 1.52% vs. 21.8% +/- 2. 19%; P < 0.005). Results of univariate and multivariate analyses confirmed that LBTT was critical in determining the percentage of DCA in serum and showed that 7alpha-DH activity and apparent distal colonic pH were also significant independent variables.

Conclusions: Slow colonic transit (more time), increased Gram-positive anaerobes (more bacteria), and greater 7alpha-DH activity (more enzyme) favor enhanced DCA formation; transit-induced increases in distal colonic luminal pH favor enhanced DCA solubilization/bioavailability; and increases in LBTT (more time) again favor DCA absorption.

MeSH terms

  • Adult
  • Aged
  • Amidohydrolases / metabolism
  • Bacteria, Anaerobic / isolation & purification
  • Bile Acids and Salts / metabolism
  • Cholelithiasis / metabolism
  • Cholelithiasis / physiopathology*
  • Cholesterol / metabolism*
  • Colon / enzymology
  • Colon / metabolism*
  • Colon / microbiology
  • Deoxycholic Acid / biosynthesis*
  • Deoxycholic Acid / blood
  • Fasting / blood
  • Gastrointestinal Transit / physiology*
  • Humans
  • Hydrogen-Ion Concentration
  • Hydroxysteroid Dehydrogenases*
  • Intestine, Large / physiopathology
  • Middle Aged
  • Oxidoreductases*
  • Steroid Hydroxylases / metabolism

Substances

  • Bile Acids and Salts
  • Deoxycholic Acid
  • Cholesterol
  • Oxidoreductases
  • Hydroxysteroid Dehydrogenases
  • 7 alpha-hydroxysteroid dehydrogenase
  • Steroid Hydroxylases
  • Amidohydrolases
  • choloylglycine hydrolase